Disruption of Type I Interferon Induction by a KSHV Homologue of IPS-1

IPS-1 的 KSHV 同系物对 I 型干扰素诱导的破坏

• 批准号: 10258718
• 负责人: DAVID JESSE SANCHEZ
• 金额: $ 34.72万
• 依托单位: WESTERN UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10258718
• 关键词: Acquired Immunodeficiency Syndrome; Adaptor Signaling Protein; Antiviral Agents; Antiviral Response; Biochemical; Cancerous; Clinical; Cloning; Dangerousness; Data; Development; Disease; Dominant-Negative Mutation; Endothelial Cells; Genes; Genome; Goals; Herpesviridae Infections; Homologous Gene; Human; Human Herpesvirus 8; Immune; Immune signaling; Immunocompromised Host; Immunologic Receptors; Impairment; Individual; Infection; Innate Immune Response; Innate Immune System; Interferon Type I; Interferons; Kaposi Sarcoma; Laboratories; Lead; Malignant Neoplasms; Maps; Names; Natural Immunity; Nucleic Acids; Open Reading Frames; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Production; Proteins; Research; Role; Severities; Signal Induction; Signal Transduction; Signaling Protein; System; TNF receptor-associated factor 3; Viral; Viral Proteins; Virus; Virus Diseases; Virus Replication; Work; cytokine; immune activation; immunoregulation; lytic replication; novel; pathogen; tumor

Project Abstract Herpes infections represent one of the most common viral infections that exists in the world. These viruses can be subclinical or as in the case of Kaposi’s Sarcoma Associated Herpesvirus (KSHV) they can lead to dangerous diseases such as cancer. KSHV is well known in AIDS patients to cause Kaposi’s Sarcoma (KS) and several other lymphoproliferartive diseases. Type I Interferon is well known to be the body’s natural anti- viral system and almost all viruses that cause infection in humans have devolved ways to block or use this system to enhance their replication in the host. We have found a novel ORF within the genome of KSHV that seems to be a viral homologue of the IPS1 protein, a critical adaptor of the Type I Interferon induction pathway. This protein is highly expressed during KSHV lytic viral replication. The overall goal of this application is to determine how KSHV uses this novel viral protein to manipulate the innate immune system that should normally limit KSHV replication. In the first specific aim, we will focus on determining how KSHV uses this gene to disrupt IFN as well as replicate efficiently. In the second aim, we plan to determine the importance of this novel gene by the construction and characterization of a KSHV deficient in this viral homologue of IPS1. The long-term goal of this project is to determine how KSHV immune modulation occurs in the goal of blocking this manipulation and limiting KSHV replication.

项目摘要 疱疹感染是世界上存在的最常见的病毒感染之一。这些病毒 可以是亚临床的，或者就像卡波西肉瘤相关疱疹病毒(KSHV)那样，它们可以导致 危险的疾病，如癌症。众所周知，KSHV在艾滋病患者中会导致卡波西肉瘤(KS) 以及其他几种淋巴增生性疾病。众所周知，I型干扰素是人体天然的抗干扰素 病毒系统和几乎所有导致人类感染的病毒都有阻止或使用这种病毒的方法 系统来增强它们在主机中的复制。我们在KSHV基因组中发现了一个新的ORF 似乎是IPS1蛋白的病毒同源物，IPS1蛋白是I型干扰素诱导途径的关键适配器。 该蛋白在KSHV裂解病毒复制过程中高度表达。此应用程序的总体目标是 确定KSHV如何使用这种新的病毒蛋白来操纵应该 通常限制KSHV复制。在第一个具体目标中，我们将重点确定KSHV如何利用这一点 基因干扰干扰素，并有效复制。在第二个目标中，我们计划确定 通过构建和鉴定IPS1的这种病毒同源物中缺失的KSHV，获得了这一新基因。 该项目的长期目标是确定KSHV免疫调节在阻断目标中是如何发生的 这种操纵和限制KSHV复制。